Inhibition of ferroptosis and iron accumulation alleviates pulmonary fibrosis in a bleomycin model
Zhuo Pei 1, Yifei Qin 2, Xianghui Fu 1, Fengfan Yang 1, Fei Huo 1, Xue Liang 1, Shijie Wang 1, Hongyong Cui 1, Peng Lin 1, Gang Zhou 1, Jiangna Yan 1, Jiao Wu 3, Zhi-Nan Chen 4, Ping Zhu 5
Redox Biol. 2022 Oct 18;57:102509. doi: 10.1016/j.redox.2022.102509.

PMID: 36302319 PMCID: PMC9614651 DOI: 10.1016/j.redox.2022.102509
Free PMC article
Abstract
Idiopathic pulmonary fibrosis (IPF) is a chronic progressive disease characterized by excessive proliferation of fibroblasts and excessive accumulation of extracellular matrix (ECM). Ferroptosis is a novel form of cell death characterized by the lethal accumulation of iron and lipid peroxidation, which is associated with many diseases. Our study addressed the potential role played by ferroptosis and iron accumulation in the progression of pulmonary fibrosis. We found that the inducers of pulmonary fibrosis and injury, namely, bleomycin (BLM) and lipopolysaccharide (LPS), induced ferroptosis of lung epithelial cells. Both the ferroptosis inhibitor liproxstatin-1 (Lip-1) and the iron chelator deferoxamine (DFO) alleviated the symptoms of pulmonary fibrosis induced by bleomycin or LPS. TGF-β stimulation upregulated the expression of transferrin receptor protein 1 (TFRC) in the human lung fibroblast cell line (MRC-5) and mouse primary lung fibroblasts, resulting in increased intracellular Fe2+, which promoted the transformation of fibroblasts into myofibroblasts. Mechanistically, TGF-β enhanced the expression and nuclear localization of the transcriptional coactivator tafazzin (TAZ), which combined with the transcription factor TEA domain protein (TEAD)-4 to promote the transcription of TFRC. In addition, elevated Fe2+ failed to induce the ferroptosis of fibroblasts, which might be related to the regulation of iron export and lipid metabolism. Finally, we specifically knocked out TFRC expression in fibroblasts in mice, and compared with those in the control mice, the symptoms of pulmonary fibrosis were reduced in the knockout mice after bleomycin induction. Collectively, these findings suggest the therapeutic potential of ferroptosis inhibitors and iron chelators in treating pulmonary fibrosis.

Keywords: Ferroptosis; Iron homeostasis; Pulmonary fibrosis; TFRC; TGF-β.

Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.

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